Effect of systemic FOLFOXIRI plus bevacizumab treatment of colorectal peritoneal metastasis on local and systemic immune cells.

Abstract

Aim: The immune system plays a crucial role in the outcome of colorectal cancer. Systemic chemotherapies modulate the immune cell composition. Little is known about these changes in peritoneal metastasized colorectal cancer. Thus, we aimed to characterize local and systemic immune cells in the course of systemic chemotherapy.

Methods: We included in total 20 patients with peritoneal metastasized colorectal cancer in our exploratory study. Initially, we investigated the peripheral blood cell distributions before and after systemic chemotherapy in a set of 11 retrospectively collected samples. Then, a prospective clinical cohort was set up to evaluate local and systemic immune cell distribution in detail (n = 9). Tumor tissue, peritoneal fluid, and peripheral blood were collected. The main immune cell subtypes were characterized using flow cytometry and immunohistochemistry, respectively.

Results: Neutrophils and the neutrophil-to-lymphocyte ratio significantly declined in response to systemic chemotherapy while circulating T cells increased (CD8⁺P = .015, CD4⁺P = .041). In peritoneal fluid, we observed a decrease of CD25⁺/FOXP3⁺/CD4⁺ regulatory T cells (P = .049) without loss of their ability to produce interferon gamma. T-cell infiltration in the tumor microenvironment showed a considerable variability between patients. However, the number of tumor-infiltrating CD8⁺ lymphocytes was not significantly changed by the application of systemic chemotherapy. Neither tumor cells nor lymphocytes or macrophages showed noteworthy expression of PD1 or PD-L1.

Conclusion: Our data show that immune cell distribution after systemic chemotherapy changes in peripheral blood. Interestingly, in peritoneal fluid only the inhibitory Treg population decreased and local T cells within peritoneal metastases remain unaffected. These data indicate little to no effect of systemic chemotherapy on the local immune system, supporting the need for new therapeutic options.